Periprosthetic seromas and athird space effect after high-dose methotrexate.

Abstract

Besides surgery, chemotherapy including high-dose methotrexate is amainstay of osteosarcoma treatment. Methotrexate is known to accumulate in tissues and cavities, so-called third spaces (e.g., periprosthetic seromas) leading to local toxicity and delayed elimination (third space effect). We compared the concentrations of methotrexate in serum and periprosthetic seromas to evaluate apotential toxic risk based on athird space effect. In 45 osteosarcoma patients who were treated with endoprosthesis and high-dose methotrexate (HDMTX) between 1991 and 2011 we retrospectively analyzed methotrexate concentrations in periprosthetic seromas and serum. Differences were assessed by means of the Wilcoxon test. A total of 112 periprosthetic seroma punctures were performed in 18out of 45patients. At 24 h the periprosthetic seroma concentrations were in median 14.86-fold (range 1.49-42.97-fold, p = 0.001), at 48 h in median 8.50-fold (range 1.36-52.56, p < 0.001) and at 72 h in median 2.66-fold (range 0.66-5.82, p = 0.015) of the corresponding serum concentrations. At 24 h highly toxic concentrations (≥ 20 μmol/l) were observed in 30% of all analyzed seromas (median 109.83 μmol/l, range 4.91-170.71 μmol/l). Asignificantly higher serum concentration (range 0.16-0.75 μmol/l, median 0.36 µmol/l) was found in patients with prior puncture than patients without puncture at 45 h after HDMTX. Methotrexate concentrations of periprosthetic seromas are significantly higher than corresponding serum concentrations possibly contributing to athird space effect. To avoid severe adverse effects punctures of these effusions should be considered.